Dysfunction of serotonin (5-HT) neurotransmission is implicated in a variety of neuropsychiatric disorders. In the treatment of depression, the primary target of antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) is 5-HT neurotransmission. However, there is significant variation in the response of patients to SSRIs with only half of patients showing full remission. Furthermore, several reports have suggested an association between SSRI treatment and an increased risk of suicide in some patients. The long-term objective of this project is to understand the interactions between 5-HT, antidepressants, and behavior. In the brain, the rate limiting step in the synthesis of 5-HT is catalyzed by the enzyme tryptophan hydroxylase 2 (Tph2). A variant in human Tph2 was recently identified in a cohort of patients with depression and predicted to reduce 5-HT synthesis by 80% based on the reduced ability of the mutant Tph2 to synthesize 5-HT when expressed in a PC12 cellular system. Interestingly, patients expressing this polymorphism were resistant to treatment with classical antidepressants, suggesting an interaction between genes and the effectiveness of antidepressant treatment. In this project, we will use mice expressing the human variant of Tph2 to test the interaction between 5-HT neurotransmission, behavior, and antidepressant response. A mouse line has already been generated by genetically engineering the human Tph2 mutation into the mouse Tph2 locus. Tph2 knock-in (Tph2 KI) mice recapitulate the predicted 80% decrease in 5-HT synthesis in various brain regions. In this proposal, the Tph2 KI mice will be treated chronically with antidepressants to determine how SSRIs affect their neurochemistry and behavioral measures of depression and anxiety as well as biochemical correlates. We will also attempt to reverse any abnormal effects of antidepressant treatment by treating the Tph2 KI mice with the 5-HT precursor, 5- hydroxytryptophan. PUBLIC HEALTH RELEVANCE: The aim of this project is to demonstrate the importance of genes in the effectiveness of antidepressant treatment. We intend to show that classical antidepressants are not the best form of treatment for patients with certain genetic mutations. In fact, patients with some genetic mutations may have adverse responses to antidepressant treatment.